The spreading popularity of topical hormone treatments in people — especially but not exclusively menopausal women — is having unintended medical consequences for the users’ pets.

Dramatic Symptoms: Brandi, a Cavalier King Charles spaniel in Los Angeles, was accidentally exposed to her owner’s hormone replacement therapy skin cream for a year beginning at 3 months of age. Recovery took a year following end of exposure

Spayed dogs and young female puppies are showing up in veterinary exam rooms with markedly swollen vulvas as if they are in heat. Male dogs present with enlarged mammary glands and abnormally small penises. Animals of both genders experience fur loss.

The problem appears to stem from the use by pet owners of hormone replacement treatments in the form of lotions, gels or sprays that are applied to the arms — especially inner elbows and wrists — or legs. The users then handle and snuggle their animals, unwittingly transferring the drug to the pets.

Symptoms of hormonal imbalance also may occur in pets that ingest the medications, either by licking where product was applied or eating an improperly stored or discarded transdermal patch or similar item.

The issue was brought to the attention of the VIN News Service by a clinician who has seen three such cases in his Bradenton, Fla., practice in the past year. The news service subsequently found that the phenomenon has been reportedanecdotally for at least five years on message boards of VIN, a professional organization and online community of veterinarians. But the cases have been described in isolation from one another, and no one has documented the incidents scientifically.

“I have never heard of this before,” Dr. Cynthia Stuenkel, an endocrinologist at the University of California, San Diego, and president of the North American Menopause Society, said when contacted by a reporter. After checking with colleagues who are leaders in the menopause field, Stuenkel reported, “Universally, people just said, ‘I have never heard of it.’ ”

Seeking to learn more, Stuenkel has begun contacting veterinarians who have seen cases and plans this weekend to raise the subject at a meeting of the executive board of the Menopause Society. She and VIN are considering a collaboration to establish a formal registry of reports, collecting uniform data that can be shared with the U.S. Food and Drug Administration (FDA).

“I think this is evolving as a potentially important finding,” Stuenkel said.

Dr. Terry Clekis, a practitioner in Bradenton, Fla., stumbled upon the phenomenon last summer when a client brought in a 3-1/2-month-old schnoodle (schnauzer-poodle mix) with an enlarged vulva. The pup had been treated by another veterinarian with antibiotics and steroids to no avail.

Clekis said he didn’t have any idea that the problem might be related to the owner using a topical hormone product. “It didn’t even enter my thought process,” he said. But a female associate, Dr. Pat Campbell, raised the possibility.

Campbell was right: The owner acknowledged using hormones on her skin.

The dog’s vulva slowly decreased in size over the course of the next month after the veterinarians recommended the owner wear gloves when applying the product and change the location of application. The schnoodle also was spayed. To lessen the pet’s exposure further, the owner ultimately moved the dog to a relative’s house.

Two months after Clekis saw the schnoodle for the first time, a 15-month-old pug named Pixie came in with the same woes. Clekis had spayed Pixie eight months earlier. His first thought was that Pixie had ovarian remnant syndrome, caused when remaining ovarian tissue in the body produces hormones that send female dogs into heat.

“I thought, oh my god, I left a little bit of the ovary in there,” Clekis said, recalling a sense of panic. “It can happen…. (But) in 27 years of practice, it hadn’t happened to me before.”

Embarrassed and rueful, Clekis scheduled the dog for a repeat spay at no charge. Fortunately, Pixie’s owner, Lisa Kuypers, is a family friend and did not seem to blame the doctor. The day of Pixie’s surgery, Kuypers went out to lunch with Clekis’s wife, Laura.

During lunch, Laura asked, “Lisa, aren’t you on a hormone cream or gel?”

Yes, she said, she was. The women grabbed a telephone and called Clekis, but it was too late. Pixie had already gone to surgery. The veterinarian found no ovarian remnants. But now he had an answer.

“Why didn’t you ask Lisa about the hormone cream?” his wife wanted to know.

“One, some women would get offended,” the veterinarian explained. “And number two, Lisa is too young.”

At 46, Kuypers is a few years from the typical age of menopause. But, she said, she had a hysterectomy in her 20s and has been taking hormone replacement drugs off and on since then; first the pill Premarin and, more recently, topical products. The medication she used when Pixie’s symptoms arose was a cream prepared by a compounding pharmacy.

Kuypers said Pixie probably picked up the drug through licking and cuddling. “I’m all the time holding her. She lays with me on the couch, and she’s all the time licking,” Kuypers said. “So it could have just got through her skin through me.”

Once she realized how risky that might be, Kuypers said, she began applying the cream to her inner thighs rather than her wrists and washing her hands afterward. About eight weeks later, she said, Pixie’s vulva was back to normal size.

When a Great Dane came into Clekis’s clinic this February looking as if she were going into heat at less than 4 months old, the veterinarian didn’t need to be reminded by his wife about the potential role of topical hormone replacement drugs. “The telltale sign is, their vulvas come in the size of Kansas,” Clekis said. “… That one we nailed pretty quick.”

Pixie is not the only dog to undergo two spay operations due to exposure to exogenous estrogen. On the other side of the country in Los Angeles, a Cavalier King Charles spaniel named Brandi had a similar experience. But in Brandi’s case, the ordeal lasted much longer. Her case was reviewed by four veterinarians before she was definitively diagnosed and could begin a recovery that took more than a year.

Meredith “Susie” Reardon bought Brandi from a breeder in Missouri in January 2008. At the time, Reardon, who is 68, was using a compounded cream containing estradiol designed to be applied to the arms twice daily. “It was such a good moisturizing cream that when I rubbed it on my arms, I’d rub it on my hands, too, like a hand cream,” Reardon said. “Who knew?”

At the same time, she held the new 3-month-old puppy “all the time,” loving her and letting the pup lick her. “Within a week,” Reardon recollected, “her little vulva just swelled up like an egg. It was so scary. Every once in a while, she would yipe and start licking herself. It did seem to be painful. That’s why everybody thought it was something (wrong) inside.”

Reardon had a 10-year-old teacup poodle as well, which she said she cuddled as much as the spaniel. But the poodle had no such symptoms.

Brandi’s regular veterinarian, Dr. Lisa Pope of Stevenson Ranch Veterinary Center in Santa Clarita, thought at first that the pup had been stung by a bee on her bottom. But when the swelling did not subside after a few days and an X-ray yielded no clues, she referred the dog to a specialty practice, Veterinary Medical and Surgical Group in Ventura, Calif.

There, Dr. Theresa Ortega, an internal medicine specialist, examined Brandi and hypothesized that the pup was excreting excess hormones. Because Brandi had not yet been spayed, Ortega figured the operation would resolve the problem.

It didn’t.

Her vulva remained grossly swollen. Fur had fallen off in a swath reaching from her hind knees and inner thighs to her stomach and chest. “Her stomach area felt like a plastic baby doll’s skin,” Reardon said. “It wasn’t soft. It wasn’t hairy. It felt like plastic.”

During Christmas 2008, Reardon’s daughter, Cindy, visited from Texas. She was shocked by the pup’s appearance. “They were trying to figure out, is it something in the food? Is it something in the yard? Is it something in the carpet? Is it something in the carpet cleaning? Everybody was at a loss,” Cindy Reardon said.

Back home in Dallas, Cindy Reardon decided to call her own vet, “the smartest person I know.” She described the case. Within minutes, the veterinarian asked, “Does your mother use hormone cream?”

“And then,” Cindy Reardon said, “it made perfect sense.”

Contacted by VIN News Service, that veterinarian said she was able to suggest a diagnosis for Brandi because she has seen at least five cases of dogs with symptoms of excess estrogen whose owners were found to be using topical hormone products. The veterinarian declined to discuss the issue in detail for this article due to time constraints.

When Reardon learned that her hormone products might be the problem, she shared the information with her gynecologist, who advised her to use the cream on her inner thighs rather than her arms. That worked fine for Reardon but didn’t seem to help Brandi.

In February 2009 during Brandi’s yearly exam with Dr. Pope, the veterinarian found the dog with a still-swollen vulva, pronounced nipple development and alopecia of the perineal area. She also discovered that Brandi had stump pyometra, an infection of leftover uterine tissue associated with excessive hormone levels. Brandi underwent a second surgery to remove the uterine stump.

In June during a follow-up visit, Brandi continued to show very high estradiol levels, Pope said. Because various treatments they’d been trying — including melatonin supplements, flax seed oil with lignans and Lysodren (mitotane), a drug used for the adrenal gland disorder Cushing’s disease — were bringing no apparent improvement, Pope referred Brandi to another specialist, Dr. David Bruyette at VCA West Los Angeles.

Bruyette thought Brandi’s problems might be caused by an adrenal enzyme defect known as 21 hydroxylase deficiency. He prescribed prednisone. At the same time, Brandi’s owner switched from hormone creams to a transdermal patch.

As Bruyette continued to monitor Brandi’s condition, two more dogs — another cavalier spaniel and a Shih tzu or Maltese — came to the hospital with similar symptoms. Bruyette determined that the dogs’ owners were using topical hormones. Not only that, he said, they were seeing the same gynecologist as Reardon: Dr. Prudence Hall of The Hall Center in Santa Monica.

Reardon described Hall as a highly recommended practitioner whose work has been featured on The Oprah Show. Hall did not respond immediately to messages from the VIN News Service seeking comment.

Three months ago, Bruyette began to withdraw Brandi from prednisone. Had her problem been an adrenal gland defect, her hormone levels would have gone back up, he said. But they continued to drop over time, which he said is strong evidence that the dog’s problems were caused by the outside exposure to hormones.

Today, two years and four months since the dog’s ordeal began, Bruyette said Brandi’s hormone levels are near normal.

Problems relating to secondary exposure to topical hormones aren’t limited to female dogs. Several cases involving male dogs have been described on VIN. One such case concerned an 8-month dachshund who presented with enlarged nipples, atrophied testicular tissue, and an underdeveloped penis when he was brought by his owner for a routine exam at Valley Veterinary Clinic in Red Bluff, Calif., last year.

The owner hadn’t recognized the abnormalities, but Dr. Debbie Fox-Chow saw them right away. “I thought he was some weird hermaphrodite type,” she said. A member of VIN, Fox-Chow searched the website and learned that accidental exposure to hormone products could be the cause.

Sure enough, when she called the owner, she learned the woman was using an estrogen-based spray. They discussed the need for the owner to use the spray on a part of her body that isn’t exposed, such as under her shirt.

One month after the hormone exposure was controlled, the dachshund developed a prostate infection. Fox-Chow said prostatitis is rare in puppies, and she believes the infection was a consequence of his prior exposure to exogenous hormones. She postponed neutering the dog until he was 9 months old to give his hormone levels a chance to return to normal.

A mother of two sons, Fox can’t help but wonder whether children, like pets, are being inadvertently exposed. “What if you’re, like, a grandmother holding a child up against you?” she said.

Such worries aren’t far-fetched. The FDA has documented cases of children being accidentally exposed to testosterone gels through contact with men undergoing male hormone replacement therapy. The men used topical hormone products on their shoulders, upper arms or stomachs.

The FDA publicized the adverse effects in an announcement in May 2009, after it had confirmed eight cases in children ranging from nine months to five years of age. Symptoms included enlargement of the genitalia, development of pubic hair, advanced bone age, increased libido and aggressive behavior, according to the statement. In at least one case, a child was hospitalized and underwent surgery due to a delay in recognizing the underlying cause.

Once the children no longer were exposed to the product, most signs and symptoms regressed, although in a few cases “enlarged genitalia did not fully return to age-appropriate size, and bone age remained modestly greater than the child’s chronological age,” the FDA news release states.

FDA does not have a public statement about the potential for adverse effects caused by secondary exposure to female topical hormone products. Asked by VIN News Service whether it was aware of the potential for such exposures, the agency said by e-mail:

“[We] have received reports of inadvertent exposure to topical estrogen products in children and pets through contact with another person being treated with the products (secondary exposure). The Center for Drug Evaluation and Research and the Center for Veterinary Medicine are evaluating these reports.”

A spokeswoman said she could not provide detail on how many such reports the FDA has received, when or by what means.

Hormone replacement therapy (HRT) is big business. The market for hormone replacement products containing estrogen was worth $1.8 billion in 2009, and topically applied drugs comprise a rapidly growing segment of that market, according to figures from SDI, a health-care analytics organization in Pennsylvania.

Since FDA-approved topical estrogen products became available in 2007, their use has grown 14-fold, with the number of prescriptions filled topping 400,000 in 2009, SDI’s data shows.

The figures likely understate the magnitude of the topical HRT market as a whole. SDI’s client base is the pharmaceutical manufacturing industry, but HRT preparations are made by compounding pharmacies, as well. Compounding pharmacies are alternate sources of medications for patients for whom commercially available, FDA-approved medications do not suffice.

The compounding side of the equation could be equal to or greater than the commercial drug side. Tom Murry, executive director of the Pharmaceutical Compounding Accreditation Board, said HRT for post-menopausal women is by far the largest of four primary segments served by the compounding industry. (The other segments are pain, pediatric and veterinary medicine.)

Drug compounding as a whole is a $10 billion to $12 billion market in the United States, according to Loyd Allen Jr., editor of the International Journal of Pharmaceutical Compounding. If, figuring conservatively, HRT comprised just one-quarter of that total, the segment would generate between $2.5 billion and $3 billion a year.

Allen said compounding of so-called bioidentical hormones began in the 1970s and ’80s, and “mushroomed” within the past eight years. The surge in popularity of compounded topical preparations can be traced to the outcome of a large clinical trial called the Women’s Health Initiative, which in 2002 found that the use of commercially available and FDA-approved HRT pills raised the risk of heart disease, stroke and breast cancer.

Whether topical hormones carry a lesser risk has not been rigorously documented, but their popularity is growing nevertheless.

Women use estrogen and related hormones to combat symptoms of menopause including hot flashes, mood swings, bone loss and diminished libido. Hormone supplementation is touted, as well, for enhancing the sense and appearance of youthfulness.

Dr. Joni Freshman, an internal medicine specialist and VIN consultant based in Colorado Springs, Colo., predicted that as baby boomers reach the age of menopause, use of such products will only continue to rise, resulting in more cases of secondary exposure. “I think it’s going to be a bigger and bigger problem,” she said.

Freshman is one of very few people well-versed in the link between topical hormone replacement therapy and exposure in household pets. Freshman traces her awareness to the early 1990s, when she diagnosed her first case in Dallas, involving a neutered male German shepherd mix.

“It had come in for a skin problem, endocrine alopecia. It had lost all its truncal hair,” she recounted.

Tests indicated that the pet had excess estrogen in his system. “I can’t tell you how much money we spent on this dog trying to figure out where all this excess estrogen was coming from,” Freshman said.

On the third or fourth visit, the owner told the veterinarian, “I put estrogen cream on my stomach and he licks it off. Could that be the problem?”

Since then, Freshman has continued intermittently to see or hear about cases either as a practitioner or in her role as a consultant to VIN and the laboratory of VCA Antech. She estimated that these days, she comes across suspect cases two or three times a month.

In spayed dogs, symptoms resembling heat such as enlarged vulvas have other potential causes, of course. There’s the rare possibility of adrenal gland problems, but the most common cause is ovarian remnant syndrome, Freshman said. She estimated that cases of ovarian remnant syndrome outnumber cases of exogenous hormone exposure 10 to one.

Dogs are not unique among pets at risk of secondary hormone exposure. Freshman knows of incidents involving cats, as well. In a recent case that came to her attention, a cat pulled discarded transdermal patches out of the trash and played with them.

Symptoms in cats differ from dogs. “They don’t have such prominent vulvas,” Freshman said. “In cats, more what I hear and see is them constantly showing clinical signs of being in heat: yowling, rolling, behavioral problems.”

Dogs and cats with high levels of estrogen may attract males of their species and submit to mating, putting them at risk for sexually transmitted diseases, Freshman said.

Overexposure to estrogens can have toxic and lasting effects in dogs and cats. Practitioners said excess estrogen can suppress the bone marrow, causing chronic anemia. It also may raise the risk of breast cancer.

Fortunately, the phenomenon is easily preventable. Users of topical hormone products simply need to be aware, and take precautions. “The biggie is that it just needs to be applied to skin covered with clothing,” Freshman said. “I tell people, ‘Put on gloves to apply it to a place where the pet won’t have any contact.’ ”

Awareness in the medical and pharmaceutical communities also is critical. Freshman advises that veterinary practitioners who see such symptoms in pets not be shy about asking all clients — regardless of gender or age — whether anyone in the household or who otherwise has contact with the pet uses a topical hormone product.

The Veterinary Information Network is considering conducting a survey to determine the prevalence of secondary exposure to pets of topical hormone products.

If you’re the veterinarian or owner of a pet that has exhibited symptoms associated with such exposure and you would like to participate in the survey, please send your name and contact information to news@vin.com

To report suspected cases to the U.S. Food and Drug Administration, please
fill out form 1932a and return to the regulatory agency.

Murry, the Pharmaceutical Compounding Accreditation Board executive director, said pharmacists likewise have a role to play. “This would be a good counseling point,” Murry said: “When you’re putting the cream on, don’t go rub somebody that you don’t want to have estrogen or testosterone (exposure), or apply the drug to a place where it’s less likely to come into contact with others.”
Stuenkel, president of the Menopause Society, said she plans this week to discuss with her colleagues the most effective way to increase awareness in the medical community of the possibility of accidental secondary exposures to topical estrogen.

“The more people we can make aware of this,” Freshman said, “the better.”